PI3K pathway is a site in human cancer cells where mutations most commonly occur and can lead to cell proliferation, activation, and signal amplification. PI3K and mTOR are the two most important kinases in the PI3K signaling pathway.
PI3 kinase (phosphatidylinositol 3-kinase, PI3Ks) belongs to the family of lipid kinases and can phosphorylate the 3′-OH terminus of the inositol ring of phosphatidylinositol. Phosphatidylinositol-3-kinase (PI3K) is a lipid kinase composed of a regulatory subunit p85 or p101 and a catalysis subunit p110 and plays a key role in cell proliferation, survival and metabolism etc. by catalyzing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to form phosphatidylinositol 3,4,5-triphosphate (PIP3) and thereby activating the downstream Akt and the like. Therefore, the inhibition of phosphatidylinositol 3-kinase may affect the PI3K pathway and thus inhibit the proliferation and activation of cancer cells.
Tumor suppressor gene PTEN (phosphatase and tension homolog deleted on chromosome ten) dephosphorylates PIP3 to generate PIP2, thus achieving negative regulation of the PI3K/Akt signaling pathway, inhibiting cell proliferation and promoting apoptosis. The frequent occurrence of PI3K gene mutation and amplification as well as the loss of PTEN in cancer and the like indicate that PI3K is closely related to tumorigenesis.
mTOR (mammalian rapamycin target protein) is a serine/threonine protein kinase present in the cytoplasm, which belongs to the phosphatidylinositol 3-kinase related kinase family and plays an important role in the regulation of signal transduction of many pathways. mTOR has been identified as a downstream target of PI3K/Akt. It has currently been found that two different mTOR complexes, i.e. mTORC1 and mTORC2, are present in the cells. They separately exercise different functions, wherein the main function of mTORC1 is to stimulate cell growth and proliferation, while mTORC2 regulates cell survival and cytoskeleton by activating AKT, PKC and other kinases. Studies have shown that the mTOR signaling pathway is related to the occurrence of cancer and the simultaneous inhibition of the activities of the two mTOR complexes in cancer cells have a more extensive and effective anti-cancer effect.
A PI3K-mTOR dual inhibitor can simultaneously block multiple segments in the signal transduction and will more effectively prevent the kinase signal transduction, thereby overcoming or delaying the emergence of drug resistance.
The patent applications W02008163636 of Novartis and W02008144463 of GSK have reported a series of compounds having an inhibition effect on both PI3K and mTOR which have good tumor therapeutic activity. However, for present there is no drug having an inhibition effect on both PI3K and mTOR in the market. Therefore, it is necessary to develop multi-targeting drugs having an inhibition effect on both PI3K and mTOR to facilitate the treatment of cancer.